This invention relates to immunomodulatory factors for use in immnunosuppressant and antiallergic treatment.
Allergic rhinitis (e.g. hayfever) and asthma are typical results of the immune system response to inhaled molecules such as allergens and antigens. It has been established that the cross-linking of antibodies initiates a series of biochemical and pharmological events including the release of potent mediators of inflammation, which results in allergic reactions, including: difficulty in breathing; itching; excess mucous secretion etc; up to and including life-threatening allergic reactions in some rare situations.
Therapeutically, many agents are used to try to prevent the release of mediators and/or to treat the downstream events by blocking or reducing the effects of the mediators on target tissues. None of the currently available treatments are ideal, and each has problems such as side effects and breakthroughs.
Immunosuppressant compounds induce an inhibition of the immune response system. The immune mediated rejection process is the major cause of graft loss in organ transplantation. Dramatic improvements in immunosuppression and subsequent organ graft and patient survival have been obtained using immunosuppressive compounds.
Autoimmune diseases are disorders where the host discrimination of xe2x80x9cselfxe2x80x9d versus xe2x80x9cnon-selfxe2x80x9d breaks down and the individual""s immune system (both acquired and innate components) attacks self tissues. Indications are that the main and fundamental error responsible for the induction and persistence of most autoimmune diseases resides within auto-reactive proliferating T lymphocytes.
The currently available immunosuppressant drugs have the disadvantage of a narrow therapeutic range. The compounds are known to be nephrotoxic, neurotoxic and potentially diabetogenic and, therefore are of limited use. Problems also exist with the administration of these compounds, their bioavailability and the monitoring of their levels both clinically and in the laboratory.
The murine trichostrongyle nematode Heligmesomoides polygyrus resists the immune system and resides in the mouse duodenum for eight months or more during primary infection. Where immunity is generated against this parasite in artificial experimental situations, it appears to be mediated by Th2 cells and their associated cytokines. However, the parasite has seemingly evolved mechanisms to counteract a potentially protective Th2 response, given the chronicity of natural infections. Simultaneously, infection with Heligmosomoides polygyrus suppresses immune responses to a variety of heterologous antigens such as ovine erythrocytes and other nematode parasites normally expelled by what we now know to be Th2 mediated immune mechanisms. Suppressive activity is also demonstrable in vivo, and in vitro using parasite extracts or excretory secretory (ES) products (Pritchard el al, Immunology (1984); 51:633-642 and Pritchard et al, Int. J. Para. (1994); 24:495-500).
The present invention is based on the isolation of an immunomodulatory factor (IMF) from the nematode Heligmosomoides polygyrus which acts to interfere with T cell function, possibly by increasing the production of CD8+ T cells with a simultaneous decrease in CD4+ T cells. Therefore, according to the present invention, an immunosuppressive agent is disclosed, wherein the agent is obtainable from the nematode Heligmosomoides polygyrus and is characterised by having a molecular weight of less than 12 kDa and being substantially free of bound polypeptides. The agent may be non-proteinaceous.
The agent may be used in the manufacture of a medicament for the treatment of allergic or autoimmune disorders. In particular, the agent may be used in the manufacture of a medicament for the prevention of graft rejection during organ or tissue transplantation. The agent may also be used in the treatment of other autoimmune disorders, for example rheumatoid arthritis and multiple sclerosis.